Tuberculosis care models for children and adolescents: a scoping review

Abstract Objective To map which tuberculosis care models are best suited for children and adolescents. Methods We conducted a scoping review to assess the impact of decentralized, integrated and family-centred care on child and adolescent tuberculosis-related outcomes, describe approaches for these care models and identify key knowledge gaps. We searched seven literature databases on 5 February 2021 (updated 16 February 2022), searched the references of 18 published reviews and requested data from ongoing studies. We included studies from countries with a high tuberculosis burden that used a care model of interest and reported tuberculosis diagnostic, treatment or prevention outcomes for an age group < 20 years old. Findings We identified 28 studies with a comparator group for the impact assessment and added 19 non-comparative studies to a qualitative analysis of care delivery approaches. Approaches included strengthening capacity in primary-level facilities, providing services in communities, screening for tuberculosis in other health services, co-locating tuberculosis and human immunodeficiency virus treatment, offering a choice of treatment location and providing social or economic support. Strengthening both decentralized diagnostic services and community linkages led to one-to-sevenfold increases in case detection across nine studies and improved prevention outcomes. We identified only five comparative studies on integrated or family-centred care, but 11 non-comparative studies reported successful treatment outcomes for at least 71% of children and adolescents. Conclusion Strengthening decentralized services in facilities and communities can improve tuberculosis outcomes for children and adolescents. Further research is needed to identify optimal integrated and family-centred care approaches.


Introduction
Of the roughly 10 million people who develop active tuberculosis annually, around one in every six is a child or adolescent aged 0-19 years old. 1,2 In 2020, less than half of the children with tuberculosis were diagnosed and treated, and only an estimated 36% of young child contacts eligible for tuberculosis preventive treatment received it. 1 When considering how to improve the detection, treatment and prevention of tuberculosis in children and adolescents, policy-makers must recognize that children and adolescents have different health care needs from adults. Tuberculosis diagnosis in children is challenging given the overlap in symptoms with common childhood illnesses, and the higher likelihood of paucibacillary and disseminated disease makes bacteriologic testing difficult. 3 Children and adolescents often access the health system differently from adults, as they may attend paediatric or youth clinics and their access may be dependent on a guardian.
Care models that remove barriers to accessing services or completing treatment can help ensure that children and adolescents are diagnosed promptly, treated effectively and receive appropriate preventive care. Three broad strategies that seek to reduce barriers are decentralization of care, integra-tion of care and family-centred care. 4 Decentralization refers to provision of services at points in the health system where patients first seek care. These points of first contact are often primary-level or community health centres, outpatient clinics or private general practitioners rather than specialized tuberculosis clinics or hospitals. Integration refers to coordinating care for multiple health conditions. Family-centred care is responsive to the needs of the family affected by tuberculosis. Important components of family-centred care are offering families a choice in what treatment they receive or how it is delivered, as well as addressing their social, psychological and economic needs.
Most of the literature evaluating decentralized, integrated or family-centred care models for tuberculosis has not specifically addressed children or adolescents. A systematic review of adherence interventions for children and adolescents showed that community-based and family-centred interventions promote successful tuberculosis disease treatment; 5 however, this review did not encompass diagnostic or prevention outcomes. Other systematic reviews have assessed the impact of community-based case-finding, 6,7 decentralized care for multidrug-resistant tuberculosis, 8 community-based treatment support, 9 integration of tuberculosis and human immunodeficiency virus (HIV) services 10,11

and socioeconomic
Objective To map which tuberculosis care models are best suited for children and adolescents. Methods We conducted a scoping review to assess the impact of decentralized, integrated and family-centred care on child and adolescent tuberculosis-related outcomes, describe approaches for these care models and identify key knowledge gaps. We searched seven literature databases on 5 February 2021 (updated 16 February 2022), searched the references of 18 published reviews and requested data from ongoing studies. We included studies from countries with a high tuberculosis burden that used a care model of interest and reported tuberculosis diagnostic, treatment or prevention outcomes for an age group < 20 years old. Findings We identified 28 studies with a comparator group for the impact assessment and added 19 non-comparative studies to a qualitative analysis of care delivery approaches. Approaches included strengthening capacity in primary-level facilities, providing services in communities, screening for tuberculosis in other health services, co-locating tuberculosis and human immunodeficiency virus treatment, offering a choice of treatment location and providing social or economic support. Strengthening both decentralized diagnostic services and community linkages led to one-to-sevenfold increases in case detection across nine studies and improved prevention outcomes. We identified only five comparative studies on integrated or family-centred care, but 11 non-comparative studies reported successful treatment outcomes for at least 71% of children and adolescents. Conclusion Strengthening decentralized services in facilities and communities can improve tuberculosis outcomes for children and adolescents. Further research is needed to identify optimal integrated and family-centred care approaches. and psychosocial support. [12][13][14] However, these reviews have not sought to disaggregate child or adolescent outcomes from adult outcomes and many of the included studies focus on adults. Because children and adolescents have unique needs based on clinical and life stage considerations, it is unclear whether the impact observed for adults translates to children and adolescents.
To address this knowledge gap, we conducted a scoping review to assess the evidence for the impact of decentralized, integrated and family-centred care on child and adolescent tuberculosis outcomes in countries with high tuberculosis burdens. Our objectives were to (i) quantitatively assess the impact of these care models on child and adolescent tuberculosis diagnosis, treatment and prevention outcomes; (ii) describe the varied approaches to implementing these care models; and (iii) identify key gaps in knowledge around the impact of these care models.

Methods
Our objectives were to map out the available evidence around a diverse set of care models and help define how these care models are being implemented in tuberculosis services for children and adolescents. We chose a scoping review because this method is more appropriate than a systematic review for exploring the definitions of decentralized, integrated and family-centred care as they apply to tuberculosis care delivery rather than assessing the evidence around a specific set of approaches defined a priori. 15 WHO staff members defined the research question for the review and commissioned an independent group of experts (CMY, HH, YHM, DS) to conduct it. This group of experts submitted a study protocol to WHO for approval before conducting the review.

Search strategy
To develop our search strategy, we first defined key features of decentralized, integrated and family-centred care in consultation with four WHO staff members and three stakeholders with experience working in middle-income country tuberculosis programmes. We developed search terms based on the results of these discussions and by consulting published systematic reviews. We searched PubMed®, Embase®, Web of Science™, WHO regional databases of the Global Index Medicus, Global Health and the Cochrane Central Register of Controlled Trials on 5 February 2021. We reviewed a sample of the first 400 abstracts and 45 articles from the database search to better define the care models, consulting stakeholders to resolve ambiguity. Based on our refined definitions, we supplemented the database search by searching the reference lists of systematic and non-systematic reviews and requesting unpublished data from ongoing studies. The development of the search strategy and search terms are available in our data repository. 16 We updated the PubMed® search on 16 February 2022, as all the included studies identified in the original database search were found in PubMed®.

Study selection
We defined seven outcomes of interest related to diagnosis (case notifications in a geographical area, diagnoses in a cohort and delay in tuberculosis diagnosis), treatment (successful treatment for tuberculosis disease) and prevention (tuberculosis preventive treatment initiation, delay in such initiation and tuberculosis preventive treatment completion among contacts). We did not include tuberculosis preventive treatment among children or adolescents living with HIV. We considered individuals aged 0-19 years, encompassing children (0-9 years) and adolescents (10-19 years). To identify feasible approaches for programmes managing large numbers of people with tuberculosis disease or exposure, we limited the review to 74 countries that either had an estimated tuberculosis incidence of ≥ 100 cases per 100 000 population in the 2020 WHO Global Tuberculosis Report (64 countries) 17 or appeared on WHO's list of tuberculosis priority countries for 2016-2020 (48 countries). 18 Two authors reviewed abstracts and full-text articles, and any disagreements were arbitrated by a third reviewer. In the abstract review, we included those that reported any outcome of interest and excluded those restricted to populations aged 18 years or older (a conventional definition of adults) since these papers would be unlikely to disaggregate data for just the adolescents 18-19 years old. In the full-text review, for the quantitative assessment, we included comparative studies that reported outcomes of interest for a group that received de-centralized, integrated or family-centred care and a group that did not. We also identified non-comparative studies for the qualitative assessment. We included articles in any language. Inclusion and exclusion criteria are available in the data repository. 16

Outcome data extraction
We extracted data on study design and setting, care model features and outcomes for available age groups within the 0-19 year range. We extracted numbers of events and people in control and intervention groups, and case notifications for intervention and pre-intervention periods in intervention and control areas. For comparative studies we performed quality assessments with the Cochrane Risk of Bias 2 tool for randomized studies or an adapted Newcastle-Ottawa scale for non-randomized studies (available in the data repository). 16

Qualitative analysis
We used a qualitative analysis approach to group interventions into general approaches for evidence synthesis. We assigned codes to intervention components, grouped codes into themes corresponding to general approaches, then grouped these approaches under the parent themes of decentralized, integrated or family-centred care models. For studies reflecting multiple care models, we categorized the study according to the predominant care model described by the authors. We included non-comparative studies in the qualitative analysis for care models where there were fewer than five comparative studies identified. While these studies would not address the impact of the care model, they could contribute to the second objective of describing care delivery approaches.

Calculation of effect estimates
We calculated risk ratios (RR) or incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs) for the child and adolescent age group. For cohort studies, we calculated RR based on count data. For studies where the outcome was case notifications, we estimated annual IRR based on case notifications during the intervention and pre-intervention periods, assuming the size of the underlying population to remain constant. Where possible, we calculated IRRs adjusted for changes in case Systematic reviews Tuberculosis care models for children and adolescents Courtney M Yuen et al. notification rate over time in a control area (i.e. the ratio of IRRs between the intervention and control area). To estimate CIs for unadjusted IRRs, we used a large-sample normal approximation. We report exact CIs for estimates based on small numbers of events. Statistical analysis was performed in SAS version 9.4 (SAS Institute Inc., Cary, United States of America).

Study identification
We reviewed 3361 abstracts from database searches and an additional 134 studies referenced by 18 reviews (Fig. 1

Decentralized care interventions
Of the 23 studies assessing the impact of a decentralized care model (Table 3), 19-39,44,46 our thematic analysis identified two major intervention approaches: strengthening services within health facilities and providing services in communities (Fig. 2). Facility-based approaches included training primarylevel providers in diagnosing and/or managing children with tuberculosis, lay-workers performing symptom screening in facilities, engaging private sector primary-level providers and making treatment services available in a more decentralized type of health facility. Community-based approaches included home visits for contact screening and community-based treatment support. Some interventions included both facility-based and community-based activities, while others included only one or the other. In addition, nine interventions included community awareness campaigns or health system strengthening through provision of supplies or procurement support to health facilities; these activities did not clearly fall into one of the care models of interest but could have contributed to improved outcomes. Most interventions received support from international funders and introduced dedicated personnel or resources into the health system.
Grouping studies by outcome and whether they contained facilitybased service strengthening, community-based services or both yielded nine groups of studies of decentralized care ( Table 3). The largest group comprised nine studies that simultaneously used facility-based interventions to improve the quality of diagnostic services in primary-level settings and communitybased interventions to increase the likelihood that children or adolescents with tuberculosis would enter the health system. [19][20][21][22][23][24][25][26]46 This combined facility and community approach consistently increased tuberculosis diagnoses in the 0-14 years age group, with effect sizes ranging from a one-to-sevenfold increase in diagnoses. In contrast, tuberculosis diagnoses did not generally increase in studies of interventions that screened people in their homes but referred them to existing health services for evaluation. 27-32 We also observed this contrast among three tuberculosis preventive treatment studies. Large increases in preventive treatment initiation were achieved in the studies that simultaneously strengthened preventive treatment services in health facilities and provided home-based screening for contacts, 38,46 but not in the study that used home-based screening alone. 39 Improved treatment outcomes in the 0-14 year age group were observed for studies that included community-based treat-

Integrated care interventions
We identified three comparative studies where integration was the primary intervention (Table 4). 40,41,45 A steppedwedge trial in Ethiopia showed that screening in integrated maternal, neonatal and child illnesses clinics increased tuberculosis diagnoses among children (0.5; 95% CI: 0.2-0.7; additional cases per clinic per 4-month period). 41 A pre-post study from Zambia showed that having antiretroviral services and tuberculosis services in the same health facilities led to increased case notifications in the 0-14 year age group (IRR: 2.67; 95% CI: 1.05-6.76). 40 A pre-post study from Kenya showed that screening in the maternal-child health, nutrition and acute care departments of a hospital did not significantly increase tuberculosis treatment registrations in the 0-14 year age group (IRR: 0.88; 95% CI: 0.44-1.77). 45 Among both comparative and non-comparative studies, integrated approaches to care included tuberculosis screening in clinics or centres for other health conditions and co-location of tuberculosis and HIV treatment (Fig. 2). Tuberculosis screening was performed in HIV clinics, maternal-child health clinics, nutrition clinics, mental health centres and a centre providing services to street-connected young people. In general, the proportion of screened children diagnosed with tuberculosis in integrated interventions was small, except for screening conducted in an HIV clinic. 24 Three non-comparative studies described delivering both tuberculosis treatment and antiretroviral therapy in a single clinic to children and adolescents living with HIV; 50-52 the proportion with successful treatment in these studies ranged from 74% to 87%.

Family-centred care interventions
We identified two comparative studies where family-centred care was the primary intervention (Table 5). A cluster-randomized trial from Peru showed that providing socioeconomic support to families affected by tuberculosis increased the proportion of contacts aged 0-19 years who initiated preventive treatment (RR: 1.70; 95% CI: 1.10-2.64). 42 An earlier pre-post study from the same setting showed that socioeconomic support improved both preventive treatment initiation (RR: 2.23; 95% CI: 2.11-2.36) and preventive treatment completion (RR: 3.22; 95% CI: 2.90-3.57). 43 Among both comparative and non-comparative studies, family-centred approaches fell into two main categories: support for patients and families; and patient choice ( Fig. 2). Support strategies included transport enablers to help people get to health facilities, food or nutritional supplements, cash transfers, support for income-generating activities, psychological counselling and establishing peer groups of people affected by tuber-

Evidence gaps
We found limited reports assessing the impact of integrated and family-centred care models on children and adolescents affected by tuberculosis, although non-comparative studies suggest that programmes are providing integrated and family-centred care to children and adolescents. Many studies that may have included children and adolescents did not sufficiently age-disaggregate data to allow assessment of child and adolescent outcomes. Even where data were agedisaggregated, the conventional use of 0-14 years as the youngest age group meant that we were unable to separate child from adolescent outcomes, and outcomes for older adolescents were generally aggregated with an adult age group.

Discussion
Our review identified a large variety of decentralized, integrated and familycentred care approaches for children and adolescents with tuberculosis disease and exposure. We found substantial evidence that simultaneously strengthening diagnostic services in decentralized health facilities and strengthening the linkages between communities and these facilities improves case detection, but doing only one or the other does not. More limited evidence suggests that strengthening decentralized preventive treatment services and providing socioeconomic support to families improves preventive treatment initiation and completion. Consistent with a previous review, 5 we found that community-based treatment support improves tuberculosis disease treatment outcomes. Finally, integrated and fam- ily-centred approaches are being used by programmes in diverse settings and are achieving good outcomes, despite a dearth of formal impact evaluations of these approaches.
Our findings highlight a couple of key considerations for the design of care models that improve child and adolescent tuberculosis outcomes. One consideration is the importance of reducing barriers simultaneously in the community and in facilities. Doing only one or the other may in some instances improve tuberculosis case detection among adults but not children, given that adults can more readily be diag-nosed by sputum testing. 29,33 However, reducing barriers in communities and facilities for the benefit of children and adolescents may benefit adults as well. 66 Another consideration is the importance of introducing new resources or workers to improve child and adolescent tuberculosis care. Funding is required to pay dedicated staff, provide transport enablers for community health workers or patients, provide supplies or equipment to health facilities or provide material support to patients and their families. When funding for these services becomes unavailable, programmatic gains may be lost. 67 If health system strengthening is incorporated into an intervention strategy, then positive impact may be maintained even after a time-limited activity (e.g. a mass community screening effort) ends. 68 Our review also identified two key priority areas for future research. One area is identifying effective integrated or family-centred care approaches for children and adolescents. Ongoing studies are evaluating the integration of tuberculosis services with child health care services 69 and shared decision-making for preventive treatment delivery location. 70 Another potential approach that could be evaluated is providing coordinated care to an entire family through shared medical appointments or counselling sessions, which could be particularly useful in the context of expanding preventive treatment to contacts of all ages. A second area is care models for adolescents. Adolescents have unique health needs that require youth-centred strategies, particularly for diseases requiring prolonged or long-term treatment. 71 Adolescent-centred strategies are being increasingly studied in the HIV field. 72,73 However, tuberculosis services have generally not yet been tailored to adolescent needs, 74,75 and our review identified only two studies that provided adolescent-centred services. 49,52 A major limitation of our review is that the lack of clear definitions for the care models of interest made develop-ment of search terms challenging. However, strengths of our approach were the iterative process used to identify relevant literature, developed in consultation with people who work in tuberculosis programmes in countries with high tuberculosis burdens and the extensive use of existing systematic reviews. Even so, it is possible that we missed studies that described the care models of interest in ways that we did not consider. Another limitation is that we did not contact authors following article identification to request age-disaggregated data given time constraints, as we had a firm deadline aligned to the inputs into the WHO consolidated guidelines on the management of tuberculosis in children and adolescents. 76 Authors of a previous systematic review of adherence support interventions for tuberculosis disease treatment in children did contact authors and consequently were able to compile a more comprehensive evidence base for this specific set of interventions. 5 Finally, we limited our review to studies from countries with high prevalence of tuberculosis in an effort to identify the most relevant interventions for these settings. However, in doing so, we likely missed studies from countries that might have had more resources to conduct research around care delivery and where tuberculosis preventive treatment for adolescents is more common.
Our findings suggest that local and international policy-makers and funders should invest in decentralized, integrated and family-centred tuberculosis services to close the large case detection and prevention gaps for children and adolescents. Policies for decentralization should articulate strategies to strengthen services in both primary-level health facilities and communities, thereby promoting linkages to tuberculosis care. Module 5 in WHO operational handbook on tuberculosis provides practical guidance for programmes seeking to implement the approaches summarized in this review. 77 Future research should focus on identifying which approaches to integrated and family-centred care for children and adolescents are effective in different settings and health systems and evaluating the impact of these approaches. When programmes identify successful approaches, decision-makers must provide resources to ensure largescale uptake and sustainability. ■ Funding: This review was supported by a grant from the WHO Global Tuberculosis Programme related to the updating of the WHO consolidated guidelines on the management of tuberculosis in children and adolescents. 76
Resultados Se identificaron 28 estudios con un grupo comparativo para la evaluación del impacto y se añadieron 19 estudios no comparativos a un análisis cualitativo de los enfoques de prestación de atención. Los enfoques incluyeron el fortalecimiento de la capacidad en los centros de nivel primario, la prestación de servicios en las comunidades, la detección de la tuberculosis en otros servicios sanitarios, la ubicación conjunta del tratamiento de la tuberculosis y del virus de la inmunodeficiencia humana, la posibilidad de que el paciente elija el lugar de tratamiento y la prestación de apoyo social o económico. El refuerzo de los servicios de diagnóstico descentralizados y de los vínculos con la comunidad permitió multiplicar de una a siete veces la detección de casos en nueve estudios y mejorar los resultados de la prevención. Solo se identificaron cinco estudios comparativos sobre la atención integrada u orientada a la familia, pero 11 estudios no comparativos informaron de resultados de tratamiento exitosos en al menos el 71% de los niños y adolescentes. Conclusión El refuerzo de los servicios descentralizados en los centros y las comunidades puede mejorar los desenlaces de la tuberculosis en niños y adolescentes. Es preciso seguir investigando para determinar los enfoques óptimos de atención integrada y orientada a la familia. (. . .continued)